Mutations of RAS/RAF Proto-oncogenes Impair Survival After Cytoreductive Surgery and HIPEC for Peritoneal Metastasis of Colorectal Origin

Abstract

BACKGROUND Adequate selection of patients with peritoneal metastasis (PM) for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) remains critical for successful long-term outcomes. Factors reflecting tumor biology are currently poorly represented in the selection process. The prognostic relevance of RAS/RAF mutations in patients with PM remains unclear. METHODS Survival data of patients with colorectal PM operated in 6 European tertiary centers were retrospectively collected and predictive factors for survival identified by Cox regression analyses. A simple point-based risk score was developed to allow patient selection and outcome prediction. RE-SULTS Data of 524 patients with a median age of 59 years and a median peritoneal cancer index of 7 (interquartile range: 3-12) were collected. A complete resection was possible in 505 patients; overall morbidity and 90-day mortality were 50.9% and 2.1%, respectively. PCI [hazard ratio (HR): 1.08], N1 stage (HR: 2.15), N2 stage (HR: 2.57), G3 stage (HR: 1.80) as well as KRAS (HR: 1.46) and BRAF (HR: 3.97) mutations were found to significantly impair survival after CRS/HIPEC on multivariate analyses. Mutations of RAS/RAF impaired survival independently of targeted treatment against EGFR. Consequently, a simple point-based risk score termed BIOSCOPE (BIOlogical Score of COlorectal PEritoneal metastasis) based on PCI, N-, G-, and RAS/RAF status was developed, which showed good discrimination [development area under the curve (AUC) = 0.72, validation AUC = 0.70], calibration (P = 0.401) and allowed categorization of patients into 4 groups with strongly divergent survival outcomes. CONCLUSION RAS/RAF mutations impair survival after CRS/HIPEC. The novel BIOSCOPE score reflects tumor biology, adequately stratifies long-term outcomes, and improves patient assessment and selection.Background: Adequate selection of patients with peritoneal metastasis (PM) for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) remains critical for successful long-term outcomes. Factors reflecting tumor biology are currently poorly represented in the selection process. The prognostic relevance of RAS/RAF mutations in patients with PM remains unclear. Methods: Survival data of patients with colorectal PM operated in 6 European tertiary centers were retrospectively collected and predictive factors for survival identified by Cox regression analyses. A simple point-based risk score was developed to allow patient selection and outcome prediction. Results: Data of 524 patients with a median age of 59 years and a median peritoneal cancer index of 7 (interquartile range: 3-12) were collected. A complete resection was possible in 505 patients; overall morbidity and 90-day mortality were 50.9% and 2.1%, respectively. PCI [hazard ratio (HR): 1.08], N1 stage (HR: 2.15), N2 stage (HR: 2.57), G3 stage (HR: 1.80) as well as KRAS (HR: 1.46) and BRAF (HR: 3.97) mutations were found to significantly impair survival after CRS/HIPEC on multivariate analyses. ...

Meta‐analysis of prognostic factors for patients with colorectal peritoneal metastasis undergoing cytoreductive surgery and heated intraperitoneal chemotherapy

“…Discordance between primary genetic mutations and those in peritoneal metastases may identify novel therapeutic targets and prognostic markers in this metastatic group. Recent research by Schneider and colleagues 65 found that RAS/RAF mutations impair survival after CRS/HIPEC, although this is the only study that has considered this prognostic factor and validation is required. Further large-scale research is needed to account for these factors; this would require collaboration between CRS + HIPEC centres, standardization of the analysis and presentation of prognostic factor time to event data.…”

CDX2: A Prognostic Marker in Metastatic Colorectal Cancer Defining a Better BRAF Mutated and a Worse KRAS Mutated Subgroup

“…BRAFmut is considered the clinically most important negative prognostic marker in mCRC (23,24). Both BRAFmut and KRASmut are poor prognostic markers after liver (25)(26)(27) and lung surgery (28) and after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (29). BRAFmut has therefore been suggested to be one of the factors to consider before metastatic surgery.…”

Dealing with insufficient liver remnant: Associating liver partition and portal vein ligation for staged hepatectomy

“…A very recent preliminary and unpublished multicenter analysis of 213 patients from 9 international ALPPS centers, which was presented at the ALPPS Expert Conference at the 2018 IHPBA Meeting in Geneva, revealed 3‐ and 5‐year survival rates of 54% and 34% (Table and Figure ). These figures compare to the 3‐ and 5‐year survival rates of 58% and 35% in a recent report on TSH with intention‐to‐treat analysis …”

“…These figures compare to the 3-and 5-year survival rates of 58% and 35% in a recent report on TSH with intention-to-treat analysis. 62,68 Chemotherapy does not only play an important role in the neoadjuvant setting before ALPPS surgery (Figure 4) but is also essential for the postoperative adjuvant treatment. This statement is supported by previous studies demonstrating that the majority of patients are embedded in a chemotherapy regimen before as well after ALPPS.…”